Following the initial observation in animal models as early as 1967, a key paper in 1974 demonstrating that high inspiratory pressures caused lung injury [1] (Fig. 1), crystallized the recognition that mechanical ventilation itself can harm the lung. Experimental models were also instrumental in showing that cyclic lung re-opening and closing creates shear stress with alveolar injury, which could be prevented by the application of positive end-expiratory pressure (PEEP) [2]. The use of computed tomography showed the response to PEEP in terms of recruitment of lung volume, giving rise to the ‘baby lung’ concept in acute respiratory distress syndrome (ARDS) [3]. Experimental models were also helpful in determining that it was not inspiratory pressure per se, but rather over-distention that caused harm leading to the concept of ‘volutrauma’ [4]. These findings led to the ‘open lung’ concept [5], which argues that a ventilation approach that prioritizes maintenance of lung volume would avoid the lung injury resulting from shear stress. Also, the concept of ‘biotrauma’ was demonstrated in an experimental model [6], whereby high-stretch ventilation generates the release of inflammatory mediators from the lung, leading to systemic inflammation and distal organ injury, particularly in the presence of zero PEEP. Two years later, these findings were validated clinically in ARDS patients.